Antigen-specific activation and proliferation of lymphocytes are regulated by both positive and negative signals from costimulatory molecules. The most extensively characterized T cell costimulatory pathway is B7-CD28, in which B7-1 (CD80) and B7-2 (CD86) each can engage the stimulatory CD28 receptor and the inhibitory CTLA-4 (CD152) receptor. In conjunction with signaling through the T cell receptor, CD28 ligation increases antigen-specific proliferation of T cells, enhances production of cytokines, stimulates differentiation and effector function, and promotes survival of T cells (Lenshow et al. (1996) Annu. Rev. Immunol. 14:233-258; Chambers and Allison (1997) Curr. Opin. Immunol. 9:396-404; and Rathmell and Thompson (1999) Annu. Rev. Immunol. 17:781-828). In contrast, signaling through CTLA-4 is thought to deliver a negative signal that inhibits T cell proliferation, IL-2 production, and cell cycle progression (Krummel and Allison (1996) J. Exp. Med. 183:2533-2540; and Walunas et al. (1996) J. Exp. Med. 183:2541-2550). Other members of the B7 family include B7-H1 (Dong et al. (1999) Nature Med. 5:1365-1369; and Freeman et al. (2000) J. Exp. Med. 192:1-9), B7-DC (Tseng et al. (2001) J. Exp. Med. 193:839-846; and Latchman et al. (2001) Nature Immunol. 2:261-268), B7-H2 (Wang et al. (2000)Blood 96:2808-2813; Swallow et al. (1999) Immunity 11:423-432; and Yoshinaga et al. (1999) Nature 402:827-832), and B7-H3 (Chapoval et al. (2001) Nature Immunol. 2:269-274). B7-H1 and B7-DC are ligands for PD-1, B7-H2 is a ligand for ICOS, and B7-H3 remains at this time an orphan ligand (Dong et al. (2003) Immunol. Res. 28:39-48).
B7 family molecules are expressed on the cell surface as homodimers with a membrane proximal constant IgC domain and a membrane distal IgV domain. Receptors for these ligands share a common extracellular IgV-like domain. Interactions of receptor-ligand pairs are mediated predominantly through residues in the IgV domains of the ligands and receptors (Schwartz et al. (2002) Nature Immunol. 3:427-434). In general, IgV domains are described as having two sheets that each contain a layer of β-strands (Williams and Barclay (1988) Annu. Rev. Immunol. 6:381-405). The front and back sheets of CTLA-4 contain strands A′GFCC′ and ABEDC,″ respectively (Ostrov et al. (2000) Science 290:816-819), whereas the front and back sheets of the B7 IgV domains are composed of strands AGFCC′C″ and BED, respectively (Schwartz et al. (2001) Nature 410:604-608; Stamper et al (2001) Nature 410:608-611; and Ikemizu et al. (2000) Immunity 12:51-60). Crystallographic analysis revealed that the CTLA-4/B7 binding interface is dominated by the interaction of the CDR3-analogous loop from CTLA-4, composed of a MYPPPY (SEQ ID NO:1) motif, with a surface on B7 formed predominately by the G, F, C, C′ and C″ strands (Schwartz et al. (2001) supra; and Stamper et al. supra). Data from amino acid homologies, mutation, and computer modeling provide support for the concept that this motif also is a major B7-binding site for CD28 (Bajorath et al. (1997) J. Mol. Graph. Model. 15:135-139). Although the MYPPPY motif is not conserved in ICOS, studies have indicated that a related motif having the sequence FDPPPF (SEQ ID NO:2) and located at the analogous position is a major determinant for binding of ICOS to B7-H2 (Wand et al. (2002) J. Exp. Med. 195:1033-1041).
B7-H1 (also called PD-L1) and B7-DC (also called PD-L2) are relatively new members of the B7 family, and have amino acid sequences that are about 34% identical to each other. Human and mouse orthologues of these molecules share about 70% amino acid identity (i.e., the human and mouse B7-H1 amino acid sequences are about 70% identical, and the human and mouse B7-DC amino acid sequences are about 70% identical). While B7-H1 and B7-DC transcripts are found in various tissues (Dong et al. (1999) supra; Latchman et al. supra; and Tamura (2001) Blood 97:1809-1816), the expression profiles of the proteins are quite distinct. Expression of B7-H1 protein, although essentially not found in normal tissues other than macrophage-like cells, can be induced in a variety of tissues and cell types (Dong et al. (1999) supra; Tamura et al. supra; and Ishida et al. (2000) Immunol. Lett. 84:57-62). In contrast, B7-DC is expressed only in dendritic cells and monocytes (Tseng et al. supra; and Ishida et al. supra).